Pregabalin is an analog of gamma-aminobutyric acid (GABA). It is useful as antiseizure therapy for central nervous system disorders such as epilepsy, Huntington's chorea, cerebral ischemia, Parkinson's disease, tardive dyskinesia, and spasticity.
Pregabalin or (S)-(+)-3-(amino methyl)-5-methylhexanoic acid, binds to the alpha-2-delta (α-δ) subunit of a calcium channel and is related to the endogenous inhibitory neurotransmitter [γ] amino butyric acid (GABA), which is involved in the regulation of brain neuronal activity. Pregabalin exhibits anti-seizure activity and is useful for treating, among other conditions, epilepsy, pain, physiological conditions associated with psychomotor stimulants, inflammation, gastrointestinal damage, alcoholism, insomnia, fibromyalgia, and various psychiatric disorders, including anxiety, depression, mania, and bipolar disorder.
Pregabalin was approved in the United States on Dec. 30, 2004, an immediate release dosage form for use in the treatment of diabetic peripheral neuropathy, postherpetic neuralgia, and as an adjunctive treatment for partial onset seizures in adults.
Pregabalin is currently available as immediate release Lyrica® in 25, 50, 75, 100, 150, 200, 225, and 300 mg hard shell capsules and is administered in patients two or three times daily (BID or TID).
The recommended dose of pregabalin is 100 mg three times a day (300 mg/day) for the treatment of neuropathic pain associated with diabetic peripheral neuropathy and post herpetic neuralgia. Pregabalin at doses of 150 to 600 mg/day is recommended for adjunctive therapy for adult patients with partial onset seizures.
To maintain reasonably stable plasma concentrations, it is necessary to resort to frequent dosing, and the resulting inconvenience to the patient often results in lowered compliance with the prescribed dosing regimen. Moreover, widely fluctuating plasma concentrations of the drug may result in administration of less than therapeutic amounts of the drug in a conservative dosing regimen, or amounts too large for the particular patient in an aggressive dosing regimen.
This type of multiple administrations leads to substantial fluctuations in the plasma concentration of the drug, especially in chronic administration.
The convenience of once daily dosing generally improves patient compliance, especially for elderly patients and for patients taking multiple medications. Once per day dosing may also lessen or prevent potentially undesirable dose-related effects by reducing peak blood levels (Cmax) and may also increase drug efficacy by increasing minimum plasma concentrations (Cmin).
Once daily dosing of pregabalin, however, presents numerous challenges as pregabalin is not absorbed uniformly in the gastrointestinal (GI) tract. Pregabalin is absorbed in the small intestine and in the ascending colon in humans.
Various approaches have been tried out for developing a once daily dosage form of pregabalin.
WO 2007/052125 A2 relates to a pharmaceutical composition comprising pregabalin, and matrix forming agent and a swelling agent, the matrix-forming agent comprising polyvinyl acetate and polyvinylpyrrolidone, and the swelling agent comprising cross-linked polyvinylpyrrolidone, wherein the pharmaceutical composition is adapted for once-daily oral dosing.
US 2005/0163848 A1 relates to a complex comprised of pregabalin and a transport moiety, such as an alkyl sulfate. The complex has an enhanced absorption in the gastrointestinal tract, particularly the lower gastrointestinal tract. The complex, and compositions and dosage forms prepared using the complex, provide for absorption by the body of the drug through a period of ten to twenty-four hours, thus enabling a once-daily dosage form for pregabalin.
US 2002/0119197 A1 relates to pharmaceutical dosage form comprising a central core including a pharmaceutical agent in a controlled-release composition, said core having two exposed opposite end surfaces and a peripheral surface at an outer edge of said core extending between said two opposed end surfaces, said peripheral edge surrounded by a diffusion-limiting sleeve, wherein said sleeve limits the diffusion of fluids into said core.
Pregabalin is a white to off-white, crystalline solid with a pKa1 of 4.2 and a pKa2 of 10.6. It is freely soluble in water and both basic and acidic aqueous solutions.
Most of the above-mentioned patent applications disclose controlled delivery systems, which utilize hydrophilic, polymeric matrices. However, for highly soluble drugs, such matrices do not provide adequate control over the drug release rate, instead resulting in a release that approximates first-order kinetics.
Thus there is need to develop stable controlled release compositions of pregabalin, which provide complete drug release and afford stable plasma levels in a once-a-day dosing regimen using hydrophobic release controlling agent(s).
A further aspect of the invention provides a solid dosage form, such as a tablet, capsules pellets, granules, powders and microtablets that are adapted for once daily oral dosing.